Prognostic Factor In Glioblastoma Patients Research Articles

Sequential Evaluation of Hematology Markers as a Prognostic Factor in Glioblastoma Patients.

In our study, we investigated the prognostic significance of hematological markers-NLR (Neutrophil-to-Lymphocyte Ratio), PLR (Platelet-to-Lymphocyte Ratio), and RDW-CV (Red Blood Cell Distribution Width-Coefficient of Variation)-in 117 glioblastoma patients. The data collected from January 2016 to December 2018 included demographics, clinical scores, and treatment regimens. Unlike previous research, which often examined these markers solely before surgery, our unique approach analyzed them at multiple stages: preoperative, postoperative, and before adjuvant therapies. We correlated these markers with the overall survival (OS) and progression-free survival (PFS) using statistical tools, including ANOVA, Cox regression, and Kaplan-Meier survival analyses, employing SPSS version 29.0. Our findings revealed notable variations in the NLR, PLR, and RDW-CV across different treatment stages. The NLR and PLR decreased after surgery, with some stabilization post-STUPP phase (NLR: p = 0.007, η2p = 0.06; PLR: p = 0.001, η2p = 0.23), while the RDW-CV increased post-surgery and during subsequent treatments (RDW-CV: p < 0.001, η2p = 0.67). Importantly, we observed significant differences between the preoperative phase and other treatment phases. Additionally, a higher NLR and RDW-CV at the second-line treatment and disease progression were associated with an increased risk of death (NLR at 2nd line: HR = 1.03, p = 0.029; RDW-CV at progression: HR = 1.14, p = 0.004). We proposed specific marker cut-offs that demonstrated significant associations with survival outcomes when applied to Kaplan-Meier survival curves (NLR at 2nd line < 5: p < 0.017; RDW-CV at progression < 15: p = 0.007). An elevated NLR and RDW-CV at later treatment stages correlated with poorer OS and PFS. No significant preoperative differences were detected. These biomarkers may serve as non-invasive tools for glioblastoma management.

Hypoxia-related THBD+ macrophages as a prognostic factor in glioma: Construction of a powerful risk model.

Glioma is a prevalent malignant tumour characterized by hypoxia as a pivotal factor in its progression. This study aims to investigate the impact of the most severely hypoxic cell subpopulation in glioma. Our findings reveal that the THBD+ macrophage subpopulation is closely associated with hypoxia in glioma, exhibiting significantly higher infiltration in tumours compared to non-tumour tissues. Moreover, a high proportion of THBD+ cells correlates with poor prognosis in glioblastoma (GBM) patients. Notably, THBD+ macrophages exhibit hypoxic characteristics and epithelial-mesenchymal transition features. Silencing THBD expression leads to a notable reduction in the proliferation and metastasis of glioma cells. Furthermore, we developed a THBD+ macrophage-related risk signature (THBDMRS) through machine learning techniques. THBDMRS emerges as an independent prognostic factor for GBM patients with a substantial prognostic impact. By comparing THBDMRS with 119 established prognostic features, we demonstrate the superior prognostic performance of THBDMRS. Additionally, THBDMRS is associated with glioma metastasis and extracellular matrix remodelling. In conclusion, hypoxia-related THBD+ macrophages play a pivotal role in glioma pathogenesis, and THBDMRS emerges as a potent and promising prognostic tool for GBM, contributing to enhanced patient survival outcomes.

ALKBH5 is a prognostic factor and promotes the angiogenesis of glioblastoma

Despite numerous reports indicating the significant impact of RNA modification on malignant glioblastoma (GBM) cell behaviors such as proliferation, invasion and therapy efficacy, its specific involvement in glioblastoma (GBM) angiogenesis is remains unclear and is currently under investigation. In this study, we aimed to investigate the relevance between RNA modification regulators and GBM angiogenesis. Our study employed bioinformatic analyses, including Gene Set Enrichment Analysis (GSEA), differential expression analysis, and Kaplan–Meier survival analysis, to identify regulators of angiogenesis-associated RNA modification (RM). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were applied to identify the enrichment of angiogenesis associated signatures in ALKBH5-high expression GBMs. We also utilized Western blot to verify the upregulation of ALKBH5 in clinical GBM samples. By a series of in vitro and in vivo assays, including plasmid transfection, wound healing, transwell invasion test, tube formation, RT-qPCR, ELISA assays and xenograft mice model, we validated the angiogenesis regulation ability of ALKBH5 in GBM. The N6-methyladenosine (m6A) modification “erase” ALKBH5 emerged as a candidate regulator associated with angiogenesis, demonstrating elevated expression and robust prognostic predictive ability in GBM patients. We also revealed enrichment of vasculature development biological process in GBMs with high ALKBH5 expression. Subsequently, we validated the elevated the expression of ALKBH5 in clinical GBM and paired adjacent tissues through western blot. Additionally, we knocked down the expression of ALKBH5 using sh-RNAs in U87 GBM cells to access the angiogenesis induction ability in U87 cells. In vitro experiments, Human Umbilical Vein Endothelial Cells (HUVECs) were used to perform wound healing, transwell migration and tube formation analysis, results indicated that ALKBH5 knock-down of U87 cells could decrease the pro-angiogenesis ability of U87 GBM cells. Further validation of our bioinformatic findings confirmed that ALKBH5 knockdown impaired VEGFA secretion in both in vitro and in vivo settings in U87 cells. These results comprehensively affirm the crucial role of ALKBH5 in regulating GBM-induced angiogenesis, both in vitro and in vivo. ALKBH5 not only emerges as a promising prognostic factor for GBM patients, but also plays a pivotal role in sustaining GBM progression by promoting angiogenesis.

LncRNA RARA-AS1 could serve as a novel prognostic biomarker in pan-cancer and promote proliferation and migration in glioblastoma

Long non-coding RNAs (lncRNAs) have emerged as crucial regulators of cancer progression and are potential biomarkers for diagnosis and treatment. This study investigates the role of RARA Antisense RNA 1 (RARA-AS1) in cancer and its implications for diagnosis and treatment. Various bioinformatics tools were conducted to analyze the expression patterns, immune-related functions, methylation, and gene expression correlations of RARA-AS1, mainly including the comparisons of different subgroups and correlation analyses between RARA-AS1 expression and other factors. Furthermore, we used short hairpin RNA to perform knockdown experiments, investigating the effects of RARA-AS1 on cell proliferation, invasion, and migration in glioblastoma. Our results revealed that RARA-AS1 has distinct expression patterns in different cancers and exhibits notable correlation with prognosis. Additionally, RARA-AS1 is highly correlated with certain immune checkpoints and mismatch repair genes, indicating its potential role in immune infiltration and related immunotherapy. Further analysis identified potential effective drugs for RARA-AS1 and demonstrated its potential RNA binding protein (RBP) mechanism in glioblastoma. Besides, a series of functional experiments indicated inhibiting RARA-AS1 could decrease cell proliferation, invasion, and migration of glioblastoma cell lines. Finally, RARA-AS1 could act as an independent prognostic factor for glioblastoma patients and may serve as a promising therapeutic target. All in all, Our study provides a comprehensive understanding of the functions and implications of RARA-AS1 in pan-cancer, highlighting it as a promising biomarker for survival. It is also an independent risk factor affecting prognosis in glioblastoma and an important factor affecting proliferation and migration in glioblastoma, setting the stage for further mechanistic investigations.

Potential Prognostic Value of GATA4 Depends on the p53 Expression in Primary Glioblastoma Patients.

Primary glioblastoma is characterized by an extremely poor prognosis. The promoter methylation of GATA4 leads to the loss of its expression in many cancer types. The formation of high-grade astrocytomas can be promoted by the concurrent loss of TP53 and GATA4 in normal human astrocytes. Nevertheless, the impact of GATA4 alterations with linkage to TP53 changes in gliomagenesis is poorly understood. This study aimed to evaluate GATA4 protein expression, GATA4 promoter methylation, p53 expression, TP53 promoter methylation, and mutation status in patients with primary glioblastoma and to assess the possible prognostic impact of these alterations on overall survival. Thirty-one patients with primary glioblastoma were included. GATA4 and p53 expressions were determined immunohistochemically, and GATA4 and TP53 promoter methylations were analyzed via methylation-specific PCR. TP53 mutations were investigated via Sanger sequencing. The prognostic value of GATA4 depends on p53 expression. Patients without GATA4 protein expression were more frequently negative for TP53 mutations and had better prognoses than the GATA4 positive patients. In patients positive for GATA4 protein expression, p53 expression was associated with the worst outcome. However, in patients positive for p53 expression, the loss of GATA4 protein expression seemed to be associated with improved prognosis. GATA4 promoter methylation was not associated with a lack of GATA4 protein expression. Our data indicate that there is a possibility that GATA4 could function as a prognostic factor in glioblastoma patients, but in connection with p53 expression. A lack of GATA4 expression is not dependent on GATA4 promoter methylation. GATA4 alone has no influence on survival time in glioblastoma patients.

Co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia predict prognosis and immunotherapy response in glioblastoma

Objectives Anesthetic drugs had been reported may impact the bio-behavior of the tumor. Propofol and sevoflurane are common anesthetics in the operation for glioblastoma (GBM). This study aims to establish a co-expression prognostic-related genes signature base on propofol and sevoflurane anesthesia to predict prognosis and immunotherapy response in GBM. Method GPM tissues with different anesthetics gene expression profiles (GSE179004) were obtained from the Gene Expression Omnibus (GEO) database. Core modules and central genes associated with propofol and sevoflurane anesthesia were identified by weighted gene coexpression network analysis (WGCNA) and establish a risk score prognostic model. Immune cell signature analysis in TCGA datasets was predicted via CIBERSORT. At last, serum methylation level of O6-methylguanine-DNA methyltransferase (MGMT) promoter was detected in GPM patient in different time during perioperative period. Results The burlywood1 group screened was significantly associated with sevoflurane-treated GBM tissue. 22 independent prognostic differential genes were construct a prognostic-related genes risk score in GBM, and showed good predictive ability. The risk score was strongly correlated with the age of the patients, but not with the sex of the patients. In addition, the differential responses to immunotherapy in high and low risk groups were analyzed, indicating that sevoflurane signature genes were consistent in the classification of gliomas. High-risk patients have high T-cell damage score and are less sensitive to immunotherapy. At last, serum methylation level of MGMT promoter was decreased in GBM patients during propofol and sevoflurane anesthesia. Conclusions Propofol and sevoflurane anesthesia associated impact on the gene expression of GBM, included the methylation level of MGMT promoter. Propofol and sevoflurane anesthesia-based risk score prognostic model, which has good prognostic power and is an independent prognostic factor in GBM patients. Therefore, this model can be used as a new biomarker for judging the prognosis of GBM patients. KEY MESSAGES Propofol and sevoflurane anesthesia-based risk score prognostic model has good prognostic power and is an independent prognostic factor in GBM patients. High Propofol and sevoflurane anesthesia-based risk score GBM patients have high T-cell damage scores and are less sensitive to immunotherapy. Serum methylation level of MGMT promoter decrease during propofol and sevoflurane anesthesia in GBM patients.

The Assessment of Clinical Outcomes and Prognostic Factors in Glioblastoma Patients.

To assess the outcomes of glioblastoma patients treated in our clinic over the last 10 years using a multimodality approach and cutting-edge techniques. In our study, we included 169 glioblastoma patients who were admitted to our clinic between 2009 and 2019 and received concurrent radiotherapy (RT) + temozolomide (TMZ) after surgery. Patients were collected retrospectively and analyzed using appropriate statistical methods. The average follow-up period was 19 months. The average overall survival (OS) was 20.5 months. PFS and PPS were found to be 10.8 and 8.9 months, respectively. In the multivariate analysis for prognostic factors on OS, the Karnofsky Performance Score (KPS), the extent of resection (EOR), and the use of adjuvant TMZ were significant. PFS was significantly predicted by KPS, EOR, adjuvant TMZ, and planning target volume (PTV). Acute severe lymphopenia (ASL) following RT reduced the OS and PFS. There was no statistical difference in OS, PFS, recurrence patterns, or ASL incidence between the RTOG and EORTC regimens and RT techniques (IMRT vs. 3D-CRT). The association between dose-volume parameters (V3, V5, V10, V15, and V20 and V25, V30, V40, and V60 Gy) and post-treatment ASL frequency was studied. For each parameter, threshold levels were discovered. Furthermore, patients with recurrent glioblastoma who received salvage therapies had better outcomes. A multidisciplinary, and intensive treatment approach using modern techniques improved the OS of glioblastoma patients. Furthermore, in glioblastoma patients, larger RT fields were not associated with better outcomes. As a result, lymphocytesparing RT may be more beneficial in increasing patients' compliance to adjuvant TMZ, which is an important prognostic factor of OS.

Comparison of Prognostic Factors in Glioblastoma Patients with Short- and Long-term Survival

Comparison of Prognostic Factors in Glioblastoma Patients with Short- and Long-term Survival

CSNK1D is associated with stemness and invasiveness in glioblastoma.

Glioblastoma (GBM) is the most common primary malignant brain tumor. It has a poor 5-year survival rate, a high recurrence rate, and few therapeutic options. Exploring the molecular processes underlying the formation and progression of GBM, as well as identifying novel therapeutic targets, is critical for improving GBM therapy and prognosis. We extracted primary GSCs (glioblastoma stem cells) from patient-derived samples. Different levels of CSNK1D were evaluated through immunohistochemistry, western blot and real-time PCR assays. A Transwell assay was used to detect invasive ability of cell lines. Tumorsphere formation assay was performed to detect cancer stemness properties. Orthotopic xenograft models were used to evaluate the effect of CSNK1D on GSC tumorigenesis. We found the expression levels of CSNK1D was elevated in GBM tissues compared with normal brain. CSNK1D expression had an increased tendency among WHO grades (G2-G4), and was higher in IDH wildtype group than in mutation group. The prognosis of the CSNK1D high expression group was significantly worse than that of the low expression group. Cox multivariate analysis showed that CSNK1D was also an independent prognostic factor in GBM patients. In primary GBM cells, we observed increased levels of CSNK1D in GSCs compared to non-stem tumor cells (NSTCs). In addition, the change of stemness markers expression and proliferation of GSCs were in coordinate with CSNK1D overexpression or knockdown. Furthermore, CSNK1D could affect the epithelial-mesenchymal transition (EMT) markers and MMPs expression in GSCs. Finally, disruption of CSNK1D expression impairs GSC survival and GBM tumor propagation in orthotopic xenograft models. Our results suggest that CSNK1D correlated with GBM prognosis and might influence the stemness and invasiveness of GSCs, which represented a potential therapeutic target in GBM patients.

BIOM-07. LOW EXPRESSION OF HLA-A AS A NOVEL PROGNOSTIC FACTOR IN GLIOBLASTOMA TREATED WITH TUMOR FUSED DENDRITIC CELL VACCINES

Abstract Although immunotherapy has become an attractive approach to cancer treatment in patients with broad types of aggressive tumors, phase III clinical trials of immunotherapy for glioblastoma (GBM) have not achieved extended survival of patients. Dendritic cells perform an essential role in the immune system as antigen-presenting cells and tumor fused dendritic cells (TFDCs) can induce tumor-specific cytotoxic T cells as a cancer vaccine. We have previously described the safety and mechanisms of TFDCs therapy, as well as immunological and clinical responses of patients with GBM, however, there were little known about predictive and prognostic biomarkers specific to TFDCs therapy. In the present study, we investigated the whole transcriptome sequencing of tumor cells, and novel prognostic factors were identified through molecular profiling GBM treated with TFDCs immunotherapy. Fifty-three patients were eligible in this study and 28 samples from patients with newly diagnosed GBM IDH wild-type were included. Of these 28 samples, 15 high-quality RNA samples successfully extracted from tumors were analysed. The samples were divided into two groups based on the median patient's overall survival. Differential expression analyses and enrichment analysis between the two groups were carried out using CLC Genomics Workbench (QIAGEN), and Gene Ontologies (GO) were assigned. A total of 473 differentially expressed genes were detected including 327 enriched GO terms. Fifteen GO terms out of 327 GO terms represented the highest enrichment scores, revealed that five GO terms were associated with the major histocompatibility complex (MHC). The relationship among the MHC, immune-related genes, and clinical outcomes was investigated using the Cox regression model and Kaplan–Meier log-rank test. Low expression of HLA-A in the tumors turned out to be a significantly favorable prognostic impact (p = 0.01). The decreased expression of HLA-A might be a novel prognostic factor in GBM patients treated with TFDCs immunotherapy.

Pyroptosis in glioblastoma: A crucial regulator of the tumour immune microenvironment and a predictor of prognosis.

Recent studies have shown that pyroptosis, an inflammatory form of cell death, has a dual role in tumorigenesis and tumour progression and affects the prognosis of patients; however, the role of pyroptosis in glioblastoma (GBM) is still unclear. In this study, based on GBM patients' data from two independent cohorts, we performed a comprehensive analysis of the expression and prognostic value of 33 pyroptosis‐associated genes (PAGs) in GBM, as well as their role in the tumour immune microenvironment (TIME) of GBM. We identified 29 PAGs that were differentially expressed between GBM and normal brain tissue, 18 of which were upregulated in GBM tissue. Most of the 33 PAGs were strongly correlated with the levels of immune cell infiltration. Based on the 33 PAGs, the GBM samples can be divided into two clusters (C1‐C2), with C1 having a ‘hot’ but immunosuppressive TIME and C2 having a ‘cold’ TIME, suggesting different immunotherapeutic responses in the two clusters. In addition, we identified four PAGs that were strongly associated with GBM prognosis and constructed a risk model based on these four PAGs. This risk model is an independent prognostic factor for GBM patients, and there is a different immune status between high‐ and low‐risk groups. In conclusion, this study demonstrates that pyroptosis is closely associated with the prognosis and TIME of GBM and provides an important basis for further studies on the relationship between pyroptosis and GBM.

Functional In Vitro Assessment of VEGFA/NOTCH2 Signaling Pathway and pRB Proteasomal Degradation and the Clinical Relevance of Mucolipin TRPML2 Overexpression in Glioblastoma Patients.

Glioblastoma (GBM) is the most malignant glioma with an extremely poor prognosis. It is characterized by high vascularization and its growth depends on the formation of new blood vessels. We have previously demonstrated that TRPML2 mucolipin channel expression increases with the glioma pathological grade. Herein by ddPCR and Western blot we found that the silencing of TRPML2 inhibits expression of the VEGFA/Notch2 angiogenic pathway. Moreover, the VEGFA/Notch2 expression increased in T98 and U251 cells stimulated with the TRPML2 agonist, ML2-SA1, or by enforced-TRPML2 levels. In addition, changes in TRPML2 expression or ML2-SA1-induced stimulation, affected Notch2 activation and VEGFA release. An increased invasion capability, associated with a reduced VEGF/VEGFR2 expression and increased vimentin and CD44 epithelial-mesenchymal transition markers in siTRPML2, but not in enforced-TRPML2 or ML2-SA1-stimulated glioma cells, was demonstrated. Furthermore, an increased sensitivity to Doxorubicin cytotoxicity was demonstrated in siTRPML2, whereas ML2-SA1-treated GBM cells were more resistant. The role of proteasome in Cathepsin B-dependent and -independent pRB degradation in siTRPML2 compared with siGLO cells was studied. Finally, through Kaplan-Meier analysis, we found that high TRPML2 mRNA expression strongly correlates with short survival in GBM patients, supporting TRPML2 as a negative prognostic factor in GBM patients.

Glioma Cells Acquire Stem-like Characters by Extrinsic Ribosome Stimuli.

Although glioblastoma (GBM) stem-like cells (GSCs), which retain chemo-radio resistance and recurrence, are key prognostic factors in GBM patients, the molecular mechanisms of GSC development are largely unknown. Recently, several studies revealed that extrinsic ribosome incorporation into somatic cells resulted in stem cell properties and served as a key trigger and factor for the cell reprogramming process. In this study, we aimed to investigate the mechanisms underlying GSCs development by focusing on extrinsic ribosome incorporation into GBM cells. Ribosome-induced cancer cell spheroid (RICCS) formation was significantly upregulated by ribosome incorporation. RICCS showed the stem-like cell characters (number of cell spheroid, stem cell markers, and ability for trans differentiation towards adipocytes and osteocytes). In RICCS, the phosphorylation and protein expression of ribosomal protein S6 (RPS6), an intrinsic ribosomal protein, and STAT3 phosphorylation were upregulated, and involved in the regulation of cell spheroid formation. Consistent with those results, glioma-derived extrinsic ribosome also promoted GBM-RICCS formation through intrinsic RPS6 phosphorylation. Moreover, in glioma patients, RPS6 phosphorylation was dominantly observed in high-grade glioma tissues, and predominantly upregulated in GSCs niches, such as the perinecrosis niche and perivascular niche. Those results indicate the potential biological and clinical significance of extrinsic ribosomal proteins in GSC development.

P14.90 Survival outcomes and prognostic factors in glioblastoma patients treated with radiotherapy plus concomitant and adjuvant temozolomide - real-world study

Abstract BACKGROUND Glioblastoma (GBM) is the most common and aggressive primary malignant brain tumour in adults. The current standard of care for newly diagnosed GBM is maximal surgical resection, followed by radiotherapy plus concomitant and adjuvant temozolomide (TMZ). This study aimed to evaluate the survival outcomes and identify predictors of survival among these patients. MATERIAL AND METHODS We performed a single-centre retrospective analysis of GBM patients treated with radiotherapy plus concomitant and adjuvant TMZ from 2013 to 2020. The analyses of progression-free survival (PFS) and overall survival (OS), each one evaluated starting from initial diagnosis, were performed. Survival curves were estimated with the Kaplan- Meier method and compared using the log-rank test. RESULTS Fifty-eight patients were identified. The median age was 61 years (range 18- 80), 51 (88%) patients were in ECOG-PS 0–1, 6 (10%) patients had isocitrate dehydrogenase (IDH) mutation and 53 (91%) of patients had undergone debulking surgery. At a median follow-up of 21 months, median OS was 12.8 months (95% confidence interval [CI] 9.7–15.9), whereas median PFS was 9.5 months (95% CI 8.5–10.5). The 1-year survival rate was 42% and the 2-year survival rate was 10%. Grade 3 or 4 hematologic toxicity occurred in 11 (19%) patients. Twenty-five (42%) patients completed at least 6 cycles of TMZ monotherapy with statistically significant differences between this sub-group and those who weren’t able to continue TMZ monotherapy [median OS 19.3 months (95% CI 14.4–24.2) vs 10.6 months (95% CI 7.8–13.4) p&amp;lt;0.001]. ECOG-PS = 0 [median OS 16.7 months (95% CI 13.4–20.0, p=0.001)] and patients under 65 years of age [median OS 15.6 months (95% CI 12.3–18.9, p=0.02) were associated with significantly better median OS. CONCLUSION The current standard of care treatment for GBM remains poor. An important factor predictor of survival is the completion of the 6 maintenance cycles of TMZ. At baseline, ECOG PS and the patient’s age could be used to define patient prognosis.

The Multifunctional Role of EMP3 in the Regulation of Membrane Receptors Associated with IDH-Wild-Type Glioblastoma.

Epithelial membrane protein 3 (EMP3) is a tetraspan membrane protein overexpressed in isocitrate dehydrogenase-wild-type (IDH-wt) glioblastoma (GBM). Several studies reported high EMP3 levels as a poor prognostic factor in GBM patients. Experimental findings based on glioma and non-glioma models have demonstrated the role of EMP3 in the regulation of several membrane proteins known to drive IDH-wt GBM. In this review, we summarize what is currently known about EMP3 biology. We discuss the regulatory effects that EMP3 exerts on a variety of oncogenic receptors and discuss how these mechanisms may relate to IDH-wt GBM. Lastly, we enumerate the open questions towards EMP3 function in IDH-wt GBM.

A Novel Glucose Metabolism-Related Gene Signature for Overall Survival Prediction in Patients with Glioblastoma.

Introduction Glioblastoma (GBM) is one of the most frequent primary intracranial malignancies, with limited treatment options and poor overall survival rates. Alternated glucose metabolism is a key metabolic feature of tumour cells, including GBM cells. However, due to high cellular heterogeneity, accurately predicting the prognosis of GBM patients using a single biomarker is difficult. Therefore, identifying a novel glucose metabolism-related biomarker signature is important and may contribute to accurate prognosis prediction for GBM patients. Methods In this research, we performed gene set enrichment analysis and profiled four glucose metabolism-related gene sets containing 327 genes related to biological processes. Univariate and multivariate Cox regression analyses were specifically completed to identify genes to build a specific risk signature, and we identified ten mRNAs (B4GALT7, CHST12, G6PC2, GALE, IL13RA1, LDHB, SPAG4, STC1, TGFBI, and TPBG) within the Cox proportional hazards regression model for GBM. Results Depending on this glucose metabolism-related gene signature, we divided patients into high-risk (with poor outcomes) and low-risk (with satisfactory outcomes) subgroups. The results of the multivariate Cox regression analysis demonstrated that the prognostic potential of this ten-gene signature is independent of clinical variables. Furthermore, we used two other GBM databases (Chinese Glioma Genome Atlas (CGGA) and REMBRANDT) to validate this model. In the functional analysis results, the risk signature was associated with almost every step of cancer progression, such as adhesion, proliferation, angiogenesis, drug resistance, and even an immune-suppressed microenvironment. Moreover, we found that IL31RA expression was significantly different between the high-risk and low-risk subgroups. Conclusion The 10 glucose metabolism-related gene risk signatures could serve as an independent prognostic factor for GBM patients and might be valuable for the clinical management of GBM patients. The differential gene IL31RA may be a potential treatment target in GBM.

What is the role of CRP in glioblastoma?

BackgroundGlioblastoma is the most common primary malignant brain tumor in adults. Previous studies have suggested that CRP (C-reactive protein) could serve as a biomarker candidate as well as a prognostic factor in glioblastoma patients, and we here further investigate its potential role. Materials and methodsPublicly available datasets were used to compare gene expression between brain samples from glioblastoma patients and non-tumor tissue. The structure of CRP was compared between humans and rats. Glioblastoma cells from humans and rats were stained with anti-CRP. Fischer 344 rats were inoculated with syngeneic glioblastoma cells pre-coated with anti-CRP, and survival was monitored. CRP concentration in rats carrying glioblastoma was followed. ResultsCRP was upregulated on one locus on gene level in glioblastoma tissue as compared to non-tumor brain tissue, but not in glioma stem cells as compared to neural stem cells. The structure of the CRP protein was a characteristic pentamer in both humans and rats. Both human and rat glioblastoma cells were clearly positive for anti-CRP staining. Pre-coating of glioblastoma cells with anti-CRP antibodies did not affect survival in rats with intracranial tumors. Serum levels of CRP increased during tumor progression but did not reach significantly different levels. ConclusionsBoth human and rat glioblastoma cells could be stained with anti-CRP antibodies in vitro. In a syngeneic glioblastoma rat model we could see an increase in serum CRP during tumor progression, but coating glioblastoma cells with anti-CRP antibodies did not provide any survival change for the animals.

Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment.

Glioblastoma (GBM), the most aggressive form of brain cancer, is characterized by a high level of molecular heterogeneity, and infiltration by various immune and stromal cell populations. Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. We have investigated the abundance of infiltrating immune and stromal cells in silico, from gene expression profiles. Two cohorts, including in‐house normal brain and glioma samples (n = 70) and a large sample set from TCGA (n = 393), were combined into a single exploratory dataset. A third independent cohort (n = 124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. We identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes with improving prognostic models in GBM.

STMO-08 INFLUENCE OF WIDE OPENING OF THE LATERAL VENTRICLE ON SURVIVAL FOR SUPRATENTORIAL GLIOBLASTOMA PATIENTS WITH RADIOTHERAPY AND CONCOMITANT TEMOZOLOMIDE-BASED CHEMOTHERAPY

BACKGROUNDThe prognosis for glioblastoma (GBM) varies among patients. Ventricular opening during surgery has been reported as a prognostic factor for GBM patients, but the influence of ventricular opening itself on patient prognosis remains controversial.OBJECTIVEAccumulating evidence has suggested that the subventricular zone (SVZ) harbors a neural stem cell niche and is associated with gliomagenesis. Several reports have hypothesized that aggressive characteristics of GBM in contact with the SVZ may be associated with the recruitment of neural stem cells from the SVZ that have abilities associated with invasive proliferation, leading to poor prognosis. We presumed that the degree of ventricular opening would correlate with the degree of SVZresection and with prognosis in GBM patients. This study therefore investigated whether the degree of ventricular opening correlates with prognosis in GBM patients treated with the standard protocol of chemo-radiotherapy.METHODSParticipants comprised 111 patients with newly diagnosed GBM who underwent surgery and postoperative radiotherapy and TMZ-based chemotherapy from 2005 to 2018. We classified 111 patients into “No ventricular opening” (NVO), “Ventricular opening, small” (VOS; distance < 21 mm) and “Ventricular opening, wide” (VOW; distance > 21 mm) groups. We evaluated the relationship between degree of ventricular opening and prognosis using survival analyses that included other clinicopathological factors.RESULTSLog-rank testing revealed age, KPS, extent of resection, MGMT status, IDH1 mutation, and degree of ventricular opening correlated significantly with overall survival. Multivariate analysis identified the degree of ventricular opening (small vs. wide) as the most significant prognostic factor (hazard ratio = 3.674; p < 0.0001).CONCLUSIONSWe demonstrated that wide opening of the lateral ventricle (LV) contributes to longer survival compared with small opening among GBM patients. Our results indicate that wide opening of the LV may correlate with the removal of a larger proportion of tumor stem cells from the SVZ.

GENE-07. INFLUENCE OF EPIGENETIC MODULATION OF THE T-CELL REGULATORS EXPRESSION ON GLIOBLASTOMAS BY HISTONE 3 LYSINE METHYLTRANSFERASE OR DEMETHYLASE ON THE PROGNOSIS OF THE GLIOBLASTOMA PATIENTS

Abstract PURPOSE The primary aim of this study is to investigate the expression of the T cell stimulators and inhibitors as well as histone modifying enzymes in the glioblastoma cells. Based on the expression of these proteins, authors estimate the prognostic role in glioblastoma patients and also validate the known prognostic factors. MATERIALS AND METHODS Using 84 FFPE samples of glioblastoma in the pathologic archives at our institute, immunohistochemical staining for T cell stimulators (CD 27, CD 28, CD 137, OX40, ICOS), inhibitors (CTLA-4, PD-1, PD-L1, TIM3, CD200R), histone 3 lysine methyltransferase (MLL4, RIZ, EZH1, NSD2), and histone 3 lysine demethylase (KDM5c, JMJD1a, UTX, JMJD5). RESULTS Median values of the immunohistochemical staining for T cell stimulators and inhibitors were 16.3% of CD27, 10.4% of CD28, 47.5% of CD137, 52.9% of ICOS, 32.2% of OX40, 31.4% of CTLA-4, 7.2% of PD-1, 55.5% of PD-L1, 62.2% of TIM3, and 42.8% of CD200R. In multivariate analysis, increased expression of CD28 (p=0.042), CD137 (p=0.009), EZH1 (p=0.040), and decreased expression of CTLA-4 (p=0.003), PDL-1 (p=0.020) in glioblastoma cells were independently associated with longer OS as well as known prognostic factors such as young age, high KPS, wide extent of resection, PRA class, and methylated MGMT promoter. Interestingly, 42 of 43 samples (97.7%) with decreased PDL1 expression had the increased EZH1 expression, 31 of 33 samples (93.9%) with decreased CTLA4 expression had the increased RIZ expression, 25 of 26 samples (96.2%) with increased CD137 expression had the increased UTX expression, and 36 of 39 samples (92.3%) with increased CD28 expression had the increased JMJD1a expression, respectively. CONCLUSION The result of presenting study suggest that the regulators of T cell can be considered as independent prognostic factors in glioblastoma patients and the expression of these regulators can be controlled by unique histone 3 lysine methylation enzymes.